Cognitive response to testosterone replacement added to intensive lifestyle intervention in older men with obesity and hypogonadism: prespecified secondary analyses of a randomized clinical trial

Abstract

Background Both obesity and hypogonadism are common in older men which could additively exacerbate age-related declines in cognitive function. However, little is known about the effects of lifestyle intervention plus testosterone replacement therapy in this population. Objectives In this secondary analysis of the LITROS (Lifestyle Intervention and Testosterone Replacement in Obese Seniors) trial, we examined whether testosterone replacement therapy would improve cognitive function when added to intensive lifestyle intervention in older men with obesity and hypogonadism. Methods Eighty-three older, obese hypogonadal men with frailty were randomly assigned to lifestyle therapy (weight management and exercise training) plus testosterone (LT + Test) or lifestyle therapy plus placebo (LT + Pbo) for 6 mo. For this report, the primary outcome was change in the global cognition composite z score. Secondary outcomes included changes in z score subcomponents: attention/information processing, memory, executive function, and language. Changes between groups were analyzed using mixed-model repeated-measures ANCOVAs following the intention-to-treat principle. Results Global cognition z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.49 compared with 0.21; between-group difference: −0.28; 95% CI: −0.45, −0.11; Cohen's d = 0.74). Moreover, attention/information z score and memory z score increased more in the LT + Test than in the LT + Pbo group (mean change: 0.55 compared with 0.23; between-group difference: −0.32; 95% CI: −0.55, −0.09; Cohen's d = 0.49 and mean change: 0.90 compared with 0.37; between-group difference: −0.53; 95% CI: −0.93, −0.13; Cohen's d = 1.43, respectively). Multiple regression analyses showed that changes in peak oxygen consumption, strength, total testosterone, and luteinizing hormone were independent predictors of the improvement in global cognition (R2 = 0.38; P < 0.001). Conclusions These findings suggest that in the high-risk population of older men with obesity and hypogonadism, testosterone replacement may improve cognitive function with lifestyle behaviors controlled via lifestyle intervention therapy. This trial was registered at clinicaltrials.gov as NCT02367105.

Testosterone, cognitive decline and dementia in ageing men

“…The intensive lifestyle intervention consisted of a weight management program (aiming to achieve 10% weight loss at six months) and exercise training, provided to all trial participants, on top of which they were randomised to transdermal testosterone or matching placebo. In LITROS, testosterone treatment resulted in improved visuospatial performance, attention, verbal memory, and global cognition scores, compared to placebo [ 98 ]. This was a smaller study compared with the Emmelot-Vonk et al and TEAAM trials [ 95 , 97 ].…”

“…It is possible that larger and longer clinical trials may be required, and that route of administration of testosterone and differences in pharmacokinetics may be relevant [ 34 ]. It is also possible that combining testosterone with a lifestyle intervention, may provide a more informative clinical trial strategy [ 98 , 111 , 112 ].…”

“…Of note, a recent secondary analysis of the Lifestyle Intervention and Testosterone Replacement in Obese Seniors (LITROS) trial, examined the effect of transdermal testosterone compared to placebo, on a background of an intensive weight management and exercise program [ 98 ]. Participants in LITROS were older men (≥ 65 years) who were obese (BMI ≥ 30 kg/m 2 ), had baseline total testosterone concentrations < 10.4 nmol/L and had evidence of mild to moderate physical frailty.…”

Weight strategy in older adults with obesity: calorie restriction or not?

“…In the Lifestyle Intervention and Testosterone Replacement in Obese Seniors trial, the combination of lifestyle therapy (calorie restriction plus aerobic and resistance exercise) plus testosterone resulted in greater improvement in cognitive function compared with lifestyle therapy plus placebo [28 ▪ ]. Based on multiple regression analyses, changes in VO 2peak , strength, testosterone, and luteinizing hormone were independent predictors of the improvement in global cognition [28 ▪ ]. These findings suggest that in the high-risk population of older men with obesity and hypogonadism, testosterone replacement therapy may improve cognitive function with lifestyle behaviors controlled through lifestyle intervention therapy.…”

“…As the aging- and obesity-related decline in cognitive function are exacerbated by hypogonadism in older men [12], an intervention that concurrently targets all these conditions could significantly reduce the risk of cognitive impairment. In the Lifestyle Intervention and Testosterone Replacement in Obese Seniors trial, the combination of lifestyle therapy (calorie restriction plus aerobic and resistance exercise) plus testosterone resulted in greater improvement in cognitive function compared with lifestyle therapy plus placebo [28 ▪ ]. Based on multiple regression analyses, changes in VO 2peak , strength, testosterone, and luteinizing hormone were independent predictors of the improvement in global cognition [28 ▪ ].…”